This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. During the previous budget period we revealed that contrary to the initial hypothesis, ERK does not seem to directly regulate GSK3beta activity. Therefore, we decided to change direction of the project. Endoplasmic reticulum (ER) dysfunction occurs as a result of oxidative damage to the ER or accumulation of misfolded proteins in that compartment leading to ER stress. ER stress induces an evolutionary conserved unfolded protein response that provides tools to restore the normal ER function. Also, ER stress may lead to cell death. The ER stress is an important player in several neurological disease including chronic neurodegenerative conditions or stroke. However, its contribution to the pathology that evolves after traumatic spinal cord injury (SCI) is unknown at present. We propose to test the hypothesis that after SCI, ER stress contributes to demyelination by inducing death of oligodendrocytes and oligodendrocyte precursor cells. The specific aims include (i) analysis of ER stress marker expression after contusion SCI, (ii) analysis of SCI outcome in mouse mutants deficient in ER stress response pathways, (iii) identification of endogenous ER stress defenses in cultured oligodendrocytes, (iv) identification of anti-ER stress interventions for oligodendrocyte protection and improvement of ER stress outcome.